UCLA study finds link between neural
stem cell overgrowth and autism-like behavior in mice
People
with autism spectrum disorder often experience a period of accelerated brain
growth after birth. No one knows why, or whether the change is linked to any
specific behavioral changes.
A new
study by UCLA researchers demonstrates how, in pregnant mice, inflammation, a
first line defense of the immune system, can trigger an excessive division of
neural stem cells that can cause “overgrowth” in the offspring’s brain.
The
paper appears Oct. 9 in the online edition of the journal Stem Cell
Reports.
“We
have now shown that one way maternal inflammation could result in larger brains
and, ultimately, autistic behavior, is through the activation of the neural
stem cells that reside in the brain of all developing and adult mammals,” said
Dr. Harley Kornblum, the paper’s senior author and a director of the Neural
Stem Cell Research Center at UCLA’s Semel Institute
for Neuroscience and Human Behavior.
In the
study, the researchers mimicked environmental factors that could activate the
immune system — such as an infection or an autoimmune disorder — by injecting a
pregnant mouse with a very low dose of lipopolysaccharide, a toxin found in E.
coli bacteria. The researchers discovered the toxin caused an
excessive production of neural stem cells and enlarged the offspring’s’ brains.
Neural
stem cells become the major types of cells in the brain, including the neurons
that process and transmit information and the glial cells that support and
protect them.
Notably,
the researchers found that mice with enlarged brains also displayed behaviors
like those associated with autism in humans. For example, they were less likely
to vocalize when they were separated from their mother as pups, were less
likely to show interest in interacting with other mice, showed increased levels
of anxiety and were more likely to engage in repetitive behaviors like
excessive grooming.
Kornblum,
who also is a professor of psychiatry, pharmacology and pediatrics at the David
Geffen School of Medicine at UCLA, said there are many environmental factors
that can activate a pregnant woman’s immune system.
“Although
it’s known that maternal inflammation is a risk factor for some
neurodevelopmental disorders such as autism, it’s not thought to directly cause
them,” he said. He noted that autism is clearly a highly heritable disorder,
but other, non-genetic factors clearly play a role.
The
researchers also found evidence that the brain growth triggered by the immune
reaction was even greater in mice with a specific genetic mutation — a lack of
one copy of a tumor suppressor gene called phosphatase and tensin homolog, or
PTEN. The PTEN protein normally helps prevent cells from growing and dividing
too rapidly. In humans, having an abnormal version of the PTEN gene leads to
very large head size or macrocephaly, a condition that also is associated with
a high risk for autism.
“Autism
is a complex group of disorders, with a variety of causes,” Kornblum said. “Our
study shows a potential way that maternal inflammation could be one of those
contributing factors, even if it is not solely responsible, through
interactions with known risk factors.”
In
addition, the team found that the proliferation of neural stem cell and brain
overgrowth was stimulated by the activation of a specific molecular pathway. (A
pathway is a series of actions amongmolecules within a cell that
leads to a certain cell function.) This pathway involved the enzyme NADPH
oxidase, which the UCLA researchers have previously found to be associated with
neural stem cell growth.
“The
discovery of these mechanisms has identified new therapeutic targets for common
autism-associated risk factors,” said Janel Le Belle, an associate researcher
in Kornblum’s lab and the paper’s lead author. “The molecular pathways that are
involved in these processes are ones that can be manipulated and possibly even
reversed pharmacologically.
“In
agreement with past clinical findings, these data add to the significant
evidence that autism-associated brain alterations begin prenatally and continue
to evolve after birth,” she said.
Kornblum
added that the findings that neural stem cell hyper-proliferation can
contribute to autism-associated features may be somewhat surprising. “Autism
neuropathology is primarily thought of as a dysregulation of neuronal
connectivity, although the molecular and cellular means by which this occurs is
not known,” he said. “Therefore, our hypothesis — that one potential means by
which autism may develop is through an overproduction of cells in the brain,
which then results in altered connectivity — is a new way of thinking about autism
etiology.”
The
next step, the researchers say, is to determine if and how the changes they
observed lead to changes in the connections between brain cells, and if those
effects can be altered after they have happened.
The
study’s other authors were Jantzen Sperry, Amy Ngo, Yasmin Ghochani, Dan Laks,
Manuel López Aranda and Alcino Silva, all of UCLA. Support was provided by the
Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, Autism Speaks
and the National Institutes of Health (grants P50-HD-055784 and MH65756), and
other entities.
